tbuckley/cabot-search huggingface dataset:
P13.15.B ULTRA-FAST DEEP-LEARNED CNS TUMOR CLASSIFICATION DURING SURGERY
Authors: C Vermeulen, M Pages Gallego, L Kester, M Kranendonk, P Wesseling, N Verburg, P de Witt Hamer, E Kooi, L Dankmeijer, J van der Lugt, K van Baarsen, E Hoving, B Tops, J de Ridder
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Central nervous system (CNS) tumors are the most lethal category of tumors, particularly among children. Most commonly, the first line treatment of CNS tumors is neurosurgical resection of the tumor. During this procedure a delicate balance must be struck between extent of resection and risk of comorbidity. Ideally, the surgical plan is based on a detailed classification of the tumor. However this classification is often unknown at the start of the surgery. Current practice consists of preoperative imaging and intraoperative diagnosis achieved by rapid histological assessment of frozen tumor sections. However, these tests do not always result in a clear diagnosis, and are sometimes even revised based on postoperative tissue-based diagnostics. As a result, some patients require a second surgery, while others could in hindsight have been operated less radically. MATERIAL AND METHODS Nanopore sequencing enables direct detection of DNA methylation status in real time, making it ideally suited for intraoperative sequencing and molecular tumor classification. The major challenge of this approach is that the classification must be performed on very few randomly distributed sequence reads. To this end we developed Sturgeon, a neural-network training approach that delivers classification models capable of classifying 81 different CNS tumor subtypes based on sparse methylation data. Sturgeon leverages illumina 450K DNA methylation profiles to simulate millions of nanopore sequencing experiments, which are then used to train and validate classifier models. The resulting models are portable, work across patients and sequence depths and require less than a minute of computation on a laptop CPU. RESULTS We demonstrate our method to be fast enough to provide a correct diagnosis with as little as 20 to 40 minutes of sequencing in 45 out of 50 retrospective pediatric brain tumor samples. We applied Sturgeon in an intraoperative setting in 25 cases, where we consistently achieve a turnaround time of 60-90 minutes from biopsy to result with a correct molecular subclassification in 18 cases and an inconclusive result in 7 cases. CONCLUSION Sturgeon classification can be used in parallel with intraoperative frozen section histology. In cases where it agrees with the pathologist, Sturgeon offers a valuable independent confirmation, and a more detailed molecular subclassification. In the rare cases where Sturgeon disagrees with the histology diagnosis, or where the histology is inconclusive, it has the potential to prevent misdiagnoses that would result in unnecessary risk of comorbidity, or the requirement for a second surgery.
KS03.5.A COMPARING VOLUMETRIC GROWTH-RATE AND RANO CRITERIA IN DETERMINING THE RESPONSE OF MENINGIOMA TO BEVACIZUMAB THERAPY
Authors: S Borenstein, A Amiel, T Siegal, O Gal, D Limon, R Eliahu, S Yust-Katz
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Meningioma is the most prevalent primary tumor in the central nervous system (CNS). Although mostly benign, 15- 20% are aggressive and tend to recur and progress despite surgery and adjuvant radiation. Recent publications show that bevacizumab, a vascular endothelial growth factor inhibitor, effectively treats these refractory meningiomas. The standard method to monitor treatment’s effect on imaging is Response Assessment in Neuro-Oncology criteria (RANO). Recently, an alternative tool called 3D volumetric growth rate (3DVGR) has emerged as a result of significant advancements in the accuracy of volumetric measurement techniques. Our aim is to compare the effectiveness of conventional RANO criteria and the emerging 3DVGR measure in evaluating the response to bevacizumab treatment in patients with refractory meningiomas. We will also assess their correlation with clinical outcomes over a period of up to 9 months. METHODS 68 MRI scans of 20 patients with aggressive meningiomas that progressed after radiation therapy and then received Bevacizumab were evaluated. Scans were obtained from two tertiary cancer centers. For each tumor both RANO and 3DVGR were conducted in two subsequent head MRI studies acquired prior to the initiation of bevacizumab treatment and then in at least one exam within 6 months post-treatment. Measurements were obtained using PACS and BRAIN LAB software by two radiologists. RESULTS A total of 43 lesions derived from 13 males and 7 females were included in the final analysis. The mean age was 65.5; mean number of pre-radiation treatments was 2.66; mean number of pre-surgical treatments was 2.7 and mean number of bevacizumab cycles was 22.7. All lesions showed a decrease or stabilization in growth rate compared to baseline. More specifically, 34 out of 43 lesions (79%) showed a negative growth rate value indicating decrease in tumor size. Comparison of treatment response using RANO criteria was not always in concordance with the 3DVGR measurement and showed inaccurate correlation with clinical outcome. CONCLUSIONS Although widely accepted for treatment response evaluation, RANO criteria are not an accurate technique for irregularly shaped lesions. As shown in our study, for atypical meningiomas, the 3DVGR measure seems to be more precise compared to RANO criteria. Furthermore, our results show great promise for treatment of refractory meningiomas with bevacizumab.
P16.05.B SAFETY AND EFFICACY OF INTRA-CSF BIOLOGIC AGENTS IN TREATMENT OF NEOPLASTIC MENINGITIS
Authors: M Trifoi, A Appiah, K Sichinga, D Aregawi, M Glantz
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Neoplastic meningitis (NM) is an increasingly frequent, profoundly morbid, and almost invariably fatal complication of solid and hematologic malignancies. Despite multimodal therapy, median survival in randomized trials is approximately 4 months. Biologic agents are widely utilized in management of extra-CSF disease, but often have limited ability to penetrate the CSF. Intra-CSF administration of biologic agents has not been widely investigated. We describe the safety and efficacy of tumor-specific, intra-CSF biologic therapy in a large group of patients with neoplastic meningitis. MATERIAL AND METHODS We queried the database of a large, international neoplastic meningitis registry (NeMeRe) to identify patients with neoplastic meningitis who received at least one dose of neoplastic meningitis-directed therapy with a biologic agent. Detailed patient demographic, treatment, toxicity and outcome data was extracted and analyzed for the first 140 consecutive patients treated at our institution. RESULTS These 140 patients received an intrathecal biologic agent as part of a histology- and molecular profile-directed intraventricular chemotherapy treatment approach. Agents included rituximab (58 patients with lymphoma, 224 cycles), trastuzumab (42 patients with malignant primary brain tumors, 211 cycles; 15 patients with breast cancer, 149 cycles; 1 patient with esophageal cancer, 9 cycles), panitumumab (4 patients with lung cancer, 9 cycles), nivolumab (1 patient with melanoma, 5 cycles; 2 patients with breast cancer, 2 cycles; 2 patients with GBM 12 cycles; 2 patients with lung cancer, 4 cycles; 2 patients with gastric adenocarcinoma, 17 cycles; 2 patients with renal clear cell carcinoma, 17 cycles; 1 patient with AML, 2 cycles; 1 patient with multiple myeloma, 8 cycles) and alpha-interferon (10 patients with melanoma, 31 cycles; 2 patients with renal clear cell carcinoma, 18 cycles). Grade I/II toxicity occurred in 5.8% of rituximab, 3.2% of trastuzumab, 0% of panitumumab, 16.3% of nivolumab, and 3.2% of alpha-interferon containing cycles. There was no grade III toxicity. Median survivals in patients with lymphomatous meningitis (304 days), solid tumor NM from primary brain tumors (243 days), HER2 -positive breast cancer (not reached, &amp;gt;315 days), lung cancer (192 days), and melanoma (307 days) were encouraging. No difference in survival was seen between patients with and without treatment-related toxicity in any histologic group. CONCLUSION This large registry-based cohort study suggests that rituximab, trastuzumab, panitumumab, nivolumab, and alpha interferon may be safely administered into the CSF as part of a multi-agent intra-CSF treatment regimen. Survival, while very tentative, is encouraging. A prospective, multi-center evaluation of these agents in patients with neoplastic meningitis is warranted.
P02.11.A INTEGRATED GENOMIC PROﬁLING OF LONG-TERM GLIOBLASTOMA SURVIVORS
Authors: P Xu, Z Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is a fatal brain tumor, and few patients survive beyond 5 years. Therefore, a study of genomic alterations in GBM long-term survivors (LTS) is essential for insights into tumor biology and biomarker identiﬁcation. MATERIAL AND METHODS In our study, we reviewed medical records from Sun Yat-sen University Cancer Center for GBM patients received initial surgery between the years 2000 and 2018. Thirty patients with GBM had an overall survival of more than 5 years. In addition to established prognostic factors such as radiochemotherapy and total surgical excision, we sought to identify genomic alterations associated with LTS by collecting surgically resected tumor tissues and normal blood controls from 13 GBM LTS (overall survival &amp;gt; 60 months) and 19 short-term survivors (STS, overall survival &amp;lt; 24 months). We performed whole exome sequencing and transcriptome sequencing on these samples. RESULTS Our findings revealed no significant differences in the composition of driver genes between the two groups. However, mutation signature analysis indicated that the proportion of mutation signature 19 was higher in the LTS than in the STS (P=0.059). Analysis of copy number variants showed that the longer survivors group had higher copy number variants at the chromosomal level (P=0.049). At the chromosome arm level, the proportion of 19p amplification and 19q amplification in the longer survivors group was significantly higher than in the short survival group (P=0.001/0.002). And in the TCGA GBM dataset, GBM patients with 19p amplification also had a better prognosis (log-rank P=0.04). CONCLUSION In conclusion, our study identified the proportion of mutation signature 19 and amplification of 19p as potential genomic alterations that could be used as prognostic biomarkers for GBM. This study could pave the way for new therapeutic approaches to this challenging disease.
P11.78.A BIUXX
Authors: M Pantalone, A Rahbar, C Söderberg-Naucler, G Stragliotto
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is a tumor with dismal prognosis and the definition of novel therapeutic targets is a pressing matter in neuro-oncology. Several groups reported the presence of Cytomegalovirus (CMV) in GBM. This virus establish a life-long infection in the host and is able to induce the hallmarks of cancer. Thus, antiviral therapy targeting CMV may represent a valid therapeutic option for patients with GBM. Over the last 15 years we treated more than 150 patients with GBM at Karolinska Universiy Hospital with the antiviral drug valganciclovir as an add-on to standard therapy. We compared retrospectively survival of these patients with contemporary controls with similar clinical and demographic characteristics treated only with standard therapy and found that patients receiving the antiviral seemed to survive longer. In addition to the direct oncomodulatory effect of CMV in GBM cells, its reactivation may affect negatively fragile individuals such as patients with GBM. Indeed patients serologically positive for CMV survives shorter time compared to serologically negative patients. Also Goerig et al. showed that CMV may also be reactivated during irradiation of the brain and cause life threating encephalitis in as many as 48% IgG positive patients with brain tumors. This was linked to encephalopathy and to early mortality risk. Thus, a successful therapeutic strategy would be to start antiviral therapy before or concomitantly radio-chemotherapy since antiviral drugs could prevent CMV reactivation before the virus would be able to cause neurologic deterioration. MATERIAL AND METHODS we analyzed by prospectively collected serological data (IgG and IgM) for CMV of 42 patients with GBM treated with valganciclovir (n=22) or placebo (n=20) in a double blind setting before, during and after radio-chemotherapy and at 6 and 12 months follow ups. We built contingency table and performed Fisher´s exact test. RESULTS At the end of radiation therapy, 5 of 12 (41.6%) IgG positive patients in the placebo group were also IgM positive, showing an active/recent infection, while none of the 16 patients were IgM positive in the valganciclovir treated group (p=0.0067). Three of the 5 patients with CMV reactivation in the placebo group experienced also neurological deterioration and developed an early recurrence at just 3 months while none developed early recurrence in VGCV group. CONCLUSION Valgancicovir prevented CMV reactivation in patients with GBM undergoing chemo-radiotherapy in a prospective, randomize setting. Prophylactic antiviral treatment may therefore be used to prevent encephalopathy and to early mortality risk linked to CMV reactivation. The clinical value of these results will need to be confirmed in larger studies. In this regard, a randomized trial evaluating anti-CMV therapy in 220 patients with GBM (the VIGAS 2, NCT04116411) is currently ongoing at our institution.
P13.01.A POST-OPERATIVE MRI SYNTHESIS FROM PRE-OPERATIVE MRI AND POST-OPERATIVE CT USING CONDITIONAL GAN FOR THE ASSESSMENT OF DEGREE OF RESECTION
Authors: X Miao, H Chen, M Tang, Y Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Magnetic resonance imaging (MRI) is an essential part of assessing the extension of resection after craniotomy, allowing for accurate assessment of the brain. However, the application of MRI within 72 hours after surgery is limited, owing to its high cost, long time duration, and patients’ limited mobility. Besides, MRI excludes people with contraindications, including implantable electronic devices or artificial limbs, in which sceneries computerized tomography (CT) is the only available choice. To overcome these limitations, we investigated the use of a deep learning model for synthesizing post-operative MRI images. MATERIAL AND METHODS We aim to employ Cross-domain Correspondence Learning for Exemplar-based Image Translation Network (CoCosNet), an exemplar-based image translation model to synthesize T1 contrast-enhanced (T1ce) MRI images by combining post-operative T1ce and post-operative CT images. 233 cases were retrospectively collected at Sun Yat-sen University Cancer Center, who underwent complete MRI and CT scans. RESULTS After 200 epochs and a batch size of 10, CoCosNet achieved comparable results compared to other existing models, with objective indicators structural similarity index = 0.75, peak signal-to-noise ratio = 21.68, and mean absolute error = 0.007. Furthermore, assessments of the extent of resection between the true and synthesized T1ce images achieve great consistency. CONCLUSION Our study demonstrates the effectiveness of the CoCosNet deep learning model in synthesizing post-operative MRI images from pre-operative MRI and post-operative CT scans. Our quantitative analysis indicates that the synthesized images have comparable quality to real MRI images and are able to accurately assess the extent of resection. This approach has a promising future by providing a reliable alternative to traditional post-operative MRI.
P07.02.B A FATTY-ACID BASED PROBE FOR NEAR INFRARED FLUORESCENCE GUIDED SURGERY OF GLIOBLASTOMA
Authors: M Ali, P Khodakivskyi, E Goun, M L M Lamfers, C W G M Lowik, C M F Dirven, R K Balvers, L Mezzanotte
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary tumor of the brain with a median survival of 15 months. Maximal safe resection is the initial standard-of-care, but resection is limited by the diffuse invasiveness of the tumor. Fluorescence imaging has been shown to aid intra-operative tumor identification, but the current options fail to do so consistently. Recent literature has shown fatty acid (FA) metabolism and uptake to be altered in glioblastoma. For this reason, we introduce a novel, near-infrared fluorescent dye, fatty-acid indocyanine green (FA-ICG), that aims to target the enhanced fatty acid uptake of glioblastoma. We evaluate this dye in in vitro and in vivo models. MATERIAL AND METHODS FA-ICG consists of palmitic acid, a long-chain, saturated fatty acid, that has been covalently linked to indocyanine green (ICG), as described previously. We validated FA-ICG in vitro in one animal cell line and four (two primary and two recurrent) patient-derived neurosphere glioblastoma cell lines. We performed in vitro temporal uptake dynamics and oleic acid based inhibition assays for FA-ICG and ICG on all cell lines. Time uptake was investigated by starving and then incubating cells with either dye for an increasing length of time. Similarly, inhibition was tested by incubating cells with increasing concentrations of oleic acid (in addition to either FA-ICG or ICG). Subsequently, the dye was tested in an NRMI mouse model without tumor for pharmacokinetic properties. Mice were injected with the dye and blood was collected at multiple time points post-injection. Quantification of fluorescence signals in serum was performed using a fluorescent standard curve. RESULTS FA-ICG was taken up by all glioblastoma cells lines. Across all cell cultures, uptake of FA-ICG showed a stepwise increase of up to 5-30 times higher uptake (compared to uptake at baseline) when cells were starved longer, while ICG uptake showed the same trend in only three out of five cell lines (and only up to 5 times higher uptake than at baseline). Oleic acid was found to inhibit FA-ICG uptake by 40% at low concentrations and up to 80-90% at higher concentrations across all cell lines, while ICG was unaffected. In vivo pharmacokinetics showed FA-ICG to have a mean half-life of 65 minutes in blood. CONCLUSION Our findings indicate that the uptake of FA-ICG is affected by starvation and oleic acid competition across all cell lines while ICG uptake is only partially affected by starvation. In vivo pharmacokinetic shows the half-life of FA-ICG to be significantly longer than that of ICG in literature. Taken together, these findings might point to an enhanced targeting and retention mechanism of FA-ICG in glioblastoma. Therefore, these results support the further translation of FA-ICG for fluorescence guided surgery in GBM.
P03.02.B VIABLE TUMOR RECURRENCE IS A MAJOR CAUSE OF LOCAL FAILURE AFTER BEVACIZUMAB THERAPY FOR RADIATION NECROSIS IN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY
Authors: Y Cho, K Yoon, D Lee, S Song, Y Kim, C Hong, J Kim
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Bevacizumab (BVZ) is known to be effective to control radiation necrosis (RN) following stereotactic radiosurgery (SRS) for brain metastases (BMs), although treatment failure may occur. Here, we investigated the incidence and pattern of local failure after BVZ therapy for RN and its underlying biological mechanism. MATERIAL AND METHODS We conducted a retrospective analysis on 17 patients who had been treated with BVZ for RN following SRS for BMs between 2016 and 2021. In each patient, the diagnosis of RN was made based on the conventional and advanced MR with or without positron emission tomography. Median 5 cycles (range, 2-10 cycles) of BVZ (5 mg/kg) were administered at 2-week intervals. Treatment response was assessed by volumetric changes of the lesions on MR and patients’ neurological status. RESULTS Treatment response was typically brisk and substantial. Best MR response was seen at median 13 weeks (range, 3-56 weeks) after the start of BVZ with a median volume decrease of 84.5% (range, 38.7-100%) of perilesional brain edema on T2WI and of 54% (range, 2.9-100%) of contrast enhancing lesions on T1WI. Patients’ neurological status improved in 16 patients (94.1%) and was stationary in 1 (5.9%). During the median follow-up of 12 months (range, 2-60 months), delayed local failure was observed in 6 patients (35.3%) at median 10 months (range, 6-14 months) after starting BVZ treatment, where viable tumor recurrence was demonstrated in all of them. No reconstitution of RN without viable tumor was observed during the follow-up. CONCLUSION Although BVZ was highly effective to control RN following SRS for BMs, delayed local failure frequently occurs owing to viable tumor recurrence. This may imply that much predominant vascular stabilizing effect of BVZ over anti-tumor effect transiently obscures the presence of potential viable tumor cells but does not prevent them from eventual recurrence.
P03.16.A ROLE OF BRD9 IN REGULATING RADIOTHERAPY INDUCED CHANGES IN CHROMATIN ARCHITECTURE OF GBM
Authors: S A Celikkol, N Pinarbasi-Değirmenci, T Bagci-Onder
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common, formidable, and aggressive type of adult brain tumor, with a poor prognosis. The standard treatment strategies are surgical resection, followed by radiotherapy and accompanying chemotherapy. However, 90% of patients suffer from recurrence of the disease due to the radiation resistance and chemotherapy resistance of glioblastoma cells, which exacerbate the success of the treatment, and thus, resistance remains one of the most important obstacles to overcome. The advances in molecular biology revealed that therapy resistance is related with alterations in DNA repair pathways as well as epigenetic changes governed by histone modifications and chromatin remodeling. Therefore, understanding the underlying epigenetic mechanisms that are involved in the DNA damage response has the potential to develop effective therapeutic strategies. In this manner, an epigenetic drug screen is conducted to identify novel epigenetic modifiers and their inhibitors as radiosensitizers. Bromodomain containing 9 (BRD9) was selected as target modifier while iBRD9 is selected as the radiosensitizer. Inhibition of BRD9 with a common probe, iBRD9 reduced cell viability and colony formation when combined with different doses of radiotherapy. Also, as an acetylated histone reader, inhibition of BRD9 increased the number of acetylated histones as shown by Western Blotting; where Belinostat treatment served as positive control. Currently, our efforts are directed towards understanding which genes are directly targeted by BRD9 in the presence and absence of radiotherapy. To this end, we have ectopically expressed Flag-tagged BRD9 and confirmed its expression by Western Blots. We showed that BRD9 was mainly localized to nucleus. Using this tool, we will perform ChIP sequencing and reveal radiotherapy induced changes in BRD9 binding sites.